The objective of this proposal is to understand a molecular mechanism that regulates the cellular defense response to viral infection. During viral infection with DNA or RNA viruses, viral dsRNA is generated by transcription and/or replication. This dsRNA is a potent stimulus of the defense response of the cell. One of the signal pathways activated by dsRNA leads to the transcriptional induction of type I interferon genes. Interferons are cytokines that have the ability to confer resistance to viral infections, to inhibit the growth of tumorigenic cells, and to activate of a variety of immune cells. Interferons are secreted from infected cells and act to protect neighboring cells from oncoming virus. Due to the time required to produce and respond to interferon, the infected cells likely gains little benefit from interferon autocrine action. Our investigations led to the discovery of rapid defense response in the infected cell that is stimulated by dsRNA and is independent of interferon or new protein synthesis. dsRNA activates a latent transcription factor, designated the dsRNA activated factor 1 (DRAF1), that binds to a DNA target site within a subset of interferon stimulated genes. Two components of DRAF1 have been identified: Interferon Regulatory Factor -3 (IRF-3), and the histone acetylases, CBP and p300. IRF-3 normally resides in the cytoplasm of the cell, but during infection it becomes phosphorylated and subsequently accumulates in the nucleus where it binds to CBP or p300. Our hypothesis that DRAF1 induces expression of specific genes that contribute to host survival via antiviral and apoptotic mechanisms. The experiments in this proposal are designed to investigate mechanisms that regulate IRF-3 cellular localization, to identify genes that are specifically induced by DRAF1, to elucidate the mechanisms that govern the pro-apoptotic effects of DRAF1 activation, and to evaluate the function of DRAF1 in the whole animal. These studies will benefit our understanding of critical cellular responses to stress.